ArticleThe Journal of biological chemistry2012
Engineered troponin C constructs correct disease-related cardiac myofilament calcium sensitivity.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C.International journal of molecular sciences · 2023Review
- Article
- A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.Molecular biology of the cell · 2021Article
- Computational Methods Elucidate Consequences of Mutations and Post-translational Modifications on Troponin I Effective Concentration to Troponin C.The journal of physical chemistry. B · 2021Article
- Biophysical Derangements in Genetic Cardiomyopathies.Heart failure clinics · 2018Review
- Troponin C Mutations Partially Stabilize the Active State of Regulated Actin and Fully Stabilize the Active State When Paired with Δ14 TnT.Biochemistry · 2017Article
- Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.Archives of biochemistry and biophysics · 2016Review
- Designing proteins to combat disease: Cardiac troponin C as an example.Archives of biochemistry and biophysics · 2016Review
- Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.Nature communications · 2016Article
- Myofilament Calcium Sensitivity: Mechanistic Insight into TnI Ser-23/24 and Ser-150 Phosphorylation Integration.Frontiers in physiology · 2016Article
- Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I.Frontiers in physiology · 2016Article
- Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.Frontiers in physiology · 2015Article
- Cardiac troponin I tyrosine 26 phosphorylation decreases myofilament Ca2+ sensitivity and accelerates deactivation.Journal of molecular and cellular cardiology · 2014Article
- Combined troponin I Ser-150 and Ser-23/24 phosphorylation sustains thin filament Ca(2+) sensitivity and accelerates deactivation in an acidic environment.Journal of molecular and cellular cardiology · 2014Article
- Ca++-sensitizing mutations in troponin, P(i), and 2-deoxyATP alter the depressive effect of acidosis on regulated thin-filament velocity.Journal of applied physiology (Bethesda, Md. : 1985) · 2014Article
- Molecular and functional consequences of mutations in the central helix of cardiac troponin C.Archives of biochemistry and biophysics · 2014Article
- Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation?Journal of muscle research and cell motility · 2014Review
- Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review.Frontiers in physiology · 2014Review
- Article
- From stem cells to cardiomyocytes: the role of forces in cardiac maturation, aging, and disease.Progress in molecular biology and translational science · 2014Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Aberrant myofilament Ca(2+) sensitivity is commonly observed with multiple cardiac diseases, especially familial cardiomyopathies. Although the etiology of the cardiomyopathies remains unclear, improving cardiac muscle Ca(2+) sensitivity through either pharmacological or genetic approaches shows promise of alleviating the disease-related symptoms. Due to its central role as the Ca(2+) sensor for cardiac muscle contraction, troponin C (TnC) stands out as an obvious and versatile target to reset disease-associated myofilament Ca(2+) sensitivity back to normal. To test the hypothesis that aberrant myofilament Ca(2+) sensitivity and its related function can be corrected through rationally engineered TnC constructs, three thin filament protein modifications representing different proteins (troponin I or troponin T), modifications (missense mutation, deletion, or truncation), and disease subtypes (familial or acquired) were studied. A fluorescent TnC was utilized to measure Ca(2+) binding to TnC in the physiologically relevant biochemical model system of reconstituted thin filaments. Consistent with the pathophysiology, the restrictive cardiomyopathy mutation, troponin I R192H, and ischemia-induced truncation of troponin I (residues 1-192) increased the Ca(2+) sensitivity of TnC on the thin filament, whereas the dilated cardiomyopathy mutation, troponin T ΔK210, decreased the Ca(2+) sensitivity of TnC on the thin filament. Rationally engineered TnC constructs corrected the abnormal Ca(2+) sensitivities of the thin filament, reconstituted actomyosin ATPase activity, and force generation in skinned trabeculae. Thus, the present study provides a novel and versatile therapeutic strategy to restore diseased cardiac muscle Ca(2+) sensitivity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.